Role of Gut Microbiota-Derived Metabolites in Modulating Immune Responses in Colorectal Cancer
Adedoyin Elizabeth Ayodele
*
Department of Microbiology, Federal University Oye Ekiti, Ekiti State, Nigeria.
Peace Chibuogwu Ugama
Department of Medical Laboratory Science, Ebonyi State University, Abakaliki, Nigeria.
Tobiloba Philip Olatokun
Department of Public Health - Environmental Health, University of Illinois Springfield, United States.
Islam Ariremako Jimoh
Department of Microbiology, University of Ilorin, Kwara State, Nigeria.
Blessing Oluwapelumi Oyebamjji
Department of Physiology, Ekiti State University, Ado-Ekiti, Nigeria.
Raimot Efunyinka Junaid-Eko
Department of Biochemistry, Lagos State University, Ojo Lagos State, Nigeria.
*Author to whom correspondence should be addressed.
Abstract
Colorectal cancer (CRC) is a leading cause of global cancer mortality, with its incidence rising due to environmental and lifestyle factors. The gut microbiota influence CRC pathogenesis through the production of bioactive metabolites that modulate the host immune response. This case-control study integrated metabolomic and immunohistochemical analyses to investigate this relationship. We found that CRC patients (n=30) exhibited a significant dysregulation of key metabolites compared to healthy controls (n=30), with fecal butyrate depleted from 52.4 ± 14.2 µg/g to 31.5 ± 11.8 µg/g (p<0.0001) and serum deoxycholic acid (DCA) elevated from 1.2 ± 0.5 µM to 3.1 ± 1.2 µM (p<0.0001). These systemic metabolite levels were strongly correlated with the tumor immune architecture: serum butyrate showed a strong positive correlation with cytotoxic CD8⁺ T-cell density (r = +0.712, p<0.0001) and a negative correlation with immunosuppressive Tregs (r = -0.501, p=0.002), while DCA correlated negatively with CD8⁺ T-cells (r = -0.654, p<0.0001) and positively with Tregs (r = +0.598, p<0.0001). Critically, this metabolomic profile directly impacted patient survival; those with high serum butyrate had a 72% 5-year overall survival rate compared to 48% for those with low levels (HR 0.41, p=0.006). Our findings directly link a dysregulated gut metabolome, characterized by low butyrate/high DCA, to an immunosuppressive tumor microenvironment and poorer clinical outcomes, highlighting these metabolites as promising non-invasive prognostic biomarkers and potential therapeutic targets.
Keywords: Colorectal cancer, gut microbiota, metabolites, tumor microenvironment, short-chain fatty acids, butyrate, deoxycholic acid, tumor-infiltrating lymphocytes